The present invention relates to a polymeric composition containing certain specific antithrombotic prostacyclin derivatives and which has antithrombotic properties, enabling it to be used for the production of various medical appliances, notably appliances which are designed to come into contact with live blood.
Many medical prostheses and other medical appliances are made of plastics materials and are, but for one problem, in general extremely successful. The problem is that most such medical appliances provoke the formation of thrombi when they come into contact with blood and this, of course, is extremely dangerous. It is, therefore, essential that such thrombi should be prevented from forming.
In general terms, there are three ways in which the thrombi provoked by medical appliances can be prevented from forming:
(1) An antithrombotic agent may be added to the blood of the patient to alter the properties of the blood and reduce its ability to form thrombi; PA1 (2) The structure of the medical appliances themselves may be made antithrombotic; PA1 (3) The medical appliances may be made antithrombotic by incorporating into them one or more suitable antithrombotic drugs. PA1 R.sup.2 represents a C.sub.3 -C.sub.12 alkyl group or a C.sub.3 -C.sub.12 alkenyl group; and PA1 n is an integer of from 1 to 5;
Of these, method (1) is often employed in practice, administering heparin or ticlopidine as the antithrombotic agent. This is, however, systemic, rather than local, application of the drug and the patient is subjected in full measure to any side effects or disadvantages of the antithrombotic drug in question. Also, of course, the antithrombotic effect is manifested in parts of the patient's body remote from the medical appliance and the normal advantageous effects of thrombi in inhibiting hemorrhaging are also prevented. In the case of ticlopidine, in particular, it takes more than a week after administration before the blood returns to its original condition in which thrombi can form when required, and the hemorrhaging which can occur during this period can give rise to serious problems.
Method (2) involves the design of the medical appliance in such a way as to minimize any physical loci which can act as foci for the development of thrombi. Although experimental work involving the relationships between structures comprising several microphases or specific fluctuations of the surface structure and antithrombotic properties has been carried out in an attempt to employ method (2), satisfactory results have not been obtained to date and thus this method cannot be used in practice to provide an antithrombotic medical appliance.
Method (3) is superior both theoretically and also having regard to present technological abilities to both methods (1) and (2). Unfortunately, prior to the present invention, although certain medical appliances incorporating antithrombotic drugs have been made commercially, it is apparent, even on theoretical grounds, that the products so far produced commercially cannot be totally satisfactory, as explained below. Moreover, although the products are undoubtedly far better than are corresponding medical appliances which do not incorporate the antithrombotic drugs, as can be seen below, these appliances are still far from satisfactory.
Principally, three classes of drugs have been investigated with a view to incorporating them into medical appliances. These are heparin, urokinase and certain prostaglandins (notably PGE.sub.1). Medical appliances made of polyvinyl chloride incorporating either heparin or urokinase are currently available and have been used in practice.
The formation of endogenous thrombi is caused predominantly either by the coagulation factor system or by the platelet system. Heparin, on the one hand, seems to suppress the activity of the coagulation factor system but does not suppress the platelet system. As a result, the formation of thrombi by the platelet system cannot be prevented by heparin. Moreover, when a platelet system thrombus forms, anti-heparin factor is released from the thrombus, subsequently reducing the effect of the heparin. Accordingly, heparin alone has a very limited ability to prevent thrombosis. On the other hand, the activity of urokinase is to convert plasminogen to plasmin, a proteolytic enzyme which has fibrinolytic effects, and thus its effect, indirectly, is to dissolve thrombi which have already formed, but it cannot prevent the growth or formation of such thrombi. Thus, although it can have some beneficial effects on patients by gradually causing the removal of a thrombus and thereby alleviating any disorders resulting therefrom, it cannot prevent the formation of thrombi and the resulting disorders.
Attempts have also been made to use certain prostaglandins as the antithrombotic drug to be incorporated into the plastics material. For example, as described by H. Jacobs et al ["PGE.sub.1 --Heparin Conjugate Releasing Polymers", Journal of Controlled Release, 2, 313 (1985)], attempts have been made to use PGE.sub.1 in certain polymers, and, although a controlled release of the drug was achieved, fibrin and other cells still adhered to the surface, thus rendering this product unsatisfactory. When attempts were then made to overcome this problem by using a combination of heparin with the prostaglandin, the PGE.sub.1 bioactivity was reduced. Another problem that has deterred experimenters from using prostaglandin derivatives is their instability, which leads them to degrade and thus lose activity when incorporated into plastics materials.
In all of the above methods, where an active compound is incorporated in a polymer, this has been achieved by forming a coating of the active compound on the surface of the polymer, specifically, on the surface of the medical appliance formed therefrom.
There has also been a reported attempt to overcome this problem by grafting an ester of the platelet aggregation inhibitor, 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin, with a vinylic monomer, e.g. 2-hydroxyethyl methacrylate, onto a poly(ether-urethane) (Biomer) [see Chemical Abstracts, 101, (1984), 101:216336r].
We have now surprisingly found that certain prostacyclin derivatives can be incorporated into plastics materials and will maintain essentially the whole of their activity, indicating that there is little or no degradation, and will moreover be released gradually into the bloodstream when used in or in association with the living body. Unlike the majority of the prior art, in the present invention, the active compounds are dispersed throughout a polymer, which is used as or as part of a medical appliance.